Eluxadoline for Irritable Bowel Syndrome with Diarrhea
Open accessAbstract
Background Effective and safe treatments are needed for patients who have irritable bowel syndrome (IBS) with diarrhea. We conducted two phase 3 trials to assess the efficacy and safety of eluxadoline, a new oral agent with mixed opioid effects (μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist), in patients with IBS with diarrhea. Methods We randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or 52 weeks (IBS-3001 trial). The primary end point was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and from weeks 1 through 26. Results For weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg) than in the placebo group reached the primary end point (IBS-3001 trial, 23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo; P=0.01 and P=0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively, vs. 16.2%; P<0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P=0.11 and P<0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and 32.7% versus 20.2% (P=0.001 and P<0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4% and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1666 patients in the safety population (0.3%). Conclusions Eluxadoline is a new therapeutic agent that reduced symptoms of IBS with diarrhea in men and women, with sustained efficacy over 6 months in patients who received the 100-mg dose twice daily. (Funded by Furiex Pharmaceuticals, an affiliate of Allergan; IBS-3001 and IBS-3002 ClinicalTrials.gov numbers, NCT01553591 and NCT01553747 , respectively.).
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All these drugs (5-HT3 antagonists, eluxadoline, rifaximin) have demonstrated efficacy over placebo in IBS-D.
“Although all these drugs have demonstrated efficacy over placebo”
From Irritable bowel syndrome (2020) · cites this paper as [123]
The Abstract reports that some patients with IBS-D may respond to rifaximin or alosetron, and the Discussion reports eluxadoline’s superiority to placebo with treatment effects similar to those reported for those drugs. The paper discusses alosetron, but does not establish placebo-superior efficacy for 5-HT3 antagonists as a class. (LLM, conf=0.82)
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“Eluxoladine reduces diarrhea in IBS-diarrhea patients and constipation is rare (Lembo et al., 2016).”
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“Definitive treatment options are still missing in IBS patients with either diarrhea or constipation and might include from time to time dietary modification, laxatives, lubiproston, linaclotide, antidiarrhoeals, alosetron, rifaximin, eluxadoline [2-5].”
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“Two recent phase 3 eluxadoline clinical trials did demonstrate improvement in IBS quality of life, but the trials were larger (n = 2427 adults) and longer (26 or 52 weeks) and focused solely on IBS‐D patients.(7) A floor effect is a possibility in that our patients reported moderate quality of life scores at baseline.”
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“However, common side effects of eluxadoline include constipation (69) especially in elderly patients with a higher rate of comorbid hepatic/biliary tract disease (62).”
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“Eluxadoline is a peripherally acting, mixed mu- and kappa-opioid receptor agonist/delta-opioid receptor antagonist, effective in slowing intestinal transit and reducing visceral hypersensitivity [187].”
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“Indeed, other phase 3 programs conducted in patients with IBS have also reported variation in trial results despite evaluating the same drug (8,9,18,19).”
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“Opioid agonists are reported to be possibly effective for IBS-D, but adverse events related to their use are still a major concern and therefore they are still under investigation.(9,14) Tong-Xie-Yao-Fang (TXYF) is a Chinese herbal formula for the management of chronic diarrhoea accompanied by abdominal pain; it has b…”
BackgroundGuidelines on the management of irritable bowel syndrome
Pietrzak, A. M., Skrzydło-Radomańska, B., Mulak, A., Lipiński, M., Malecka-Panas, E. I., Reguła, J., & Rydzewska, G. M. (2018) · Gastroenterology Review · doi:10.5114/pg.2018.78343 · Cited by 56 · see citing works
“Only one study was conducted exclusively in men [237].”
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Common Functional Gastroenterologic Disorders Associated With Abdominal Pain
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“Somatic symptoms (eg, chronic fatigue, fibromyalgia, and cardiopulmonary symptoms) that are not due to an organic disorder and psychiatric disorders (major depression, anxiety, and somatization) are also common in patients with IBS.24,28,29 In patients with chronic abdominal pain, the prevalence of depression and impa…”
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Gargari, G., Mantegazza, G., Cremon, C., Taverniti, V., Valenza, A., Barbaro, M., Marasco, G., Duncan, R., Fiore, W., Ferrari, R., et al. (2024) · Gut microbes · doi:10.1080/19490976.2023.2298246 · Cited by 55 · see citing works
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Psychotropics, Antidepressants, and Visceral Analgesics in Functional Gastrointestinal Disorders
Törnblom, H., & Drossman, D. (2018) · Current Gastroenterology Reports · doi:10.1007/s11894-018-0664-3 · Cited by 55 · see citing works
Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use
Lacy, B., Chey, W., Cash, B., Lembo, A., Dove, L. S., & Covington, P. (2017) · American Journal of Gastroenterology · doi:10.1038/ajg.2017.72 · Cited by 55 · see citing works
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“However, loperamide, which inhibits peristalsis and increases colonic transit time, is not helpful with abdominal pain [23], and often more than a drug is necessary.”
BackgroundSinagra, E., Morreale, G., Mohammadian, G., Fusco, G., Guarnotta, V., Tomasello, G., Cappello, F., Rossi, F., Amvrosiadis, G., & Raimondo, D. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i36.6593 · Cited by 52 · see citing works
Lucak, S., Chang, L., Halpert, A., & Harris, L. (2017) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756283x16663396 · Cited by 51 · see citing works
New insights into irritable bowel syndrome: from pathophysiology to treatment
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“Loperamide can help with diarrhea by inhibiting peristalsis and increasing colonic transit time, but again it may not help with abdominal pain [106].”
BackgroundSchiller, L. (2017) · Current Gastroenterology Reports · doi:10.1007/s11894-017-0557-x · Cited by 50
Brenner, D., Sayuk, G., Gutman, C., Jo, E., Elmes, S., Liu, L. W. C., & Cash, B. (2019) · American Journal of Gastroenterology · doi:10.14309/ajg.0000000000000327 · Cited by 48 · see citing works
“In the two phase 3 studies (IBS-3001 [52-week treatment] and IBS-3002 [26-week treatment]) evaluating the safety and efficacy of eluxadoline, the primary composite endpoint was defined as a concurrent $30% improvement in daily abdominal pain score compared with baseline and a BSS score ,5 on at least 50% of days withi…”
BackgroundPharmacological Therapies and Their Clinical Targets in Irritable Bowel Syndrome With Diarrhea
Colomier, E., Algera, J., & Melchior, C. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.629026 · Cited by 47 · see citing works
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Self-citationPharmacotherapy for Irritable Bowel Syndrome
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“Three large clinical trials, involving a total of over 3000 patients randomized to eluxadoline or placebo, have demonstrated efficacy of eluxadoline in the relief of diarrhea or the composite endpoint of diarrhea and pain over 12 weeks of treatment [48,49].”
BackgroundAnwer, M., Al-Shdefat, R., Ezzeldin, E., Alshahrani, S., Alshetaili, A., & Iqbal, M. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00844 · Cited by 42
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“While a low incidence of pancreatitis with mild symptoms was also recognized (Dove et al., 2013; Lembo et al., 2016), post-marketing surveillance identi fi ed additional cases.”
BackgroundPlasse, T. F., Barton, G., Davidson, E., Abramson, D., Kalfus, I., Fathi, R., Raday, G., & Harris, M. S. (2020) · American Journal of Gastroenterology · doi:10.14309/ajg.0000000000000727 · Cited by 40 · see citing works
“The magnitude of effects was comparable with thosewith other approved products for IBS-D, alosetron (17,18), rifaximin (19), and eluxadoline (20) across all study end points.”
ResultDecraecker, L., Looze, D. D., Hirsch, D., Schepper, H. D. D., Arts, J., Caenepeel, P., Bredenoord, A., Kolkman, J., Bellens, K., Beek, K. V., et al. (2024) · Gut · doi:10.1136/gutjnl-2023-331634 · Cited by 39 · see citing works
Diabetes and the Small Intestine
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Self-citationNew advances in the treatment of paediatric functional abdominal pain disorders
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Diarrhea‐predominant irritable bowel syndrome: Diagnosis, etiology, and new treatment considerations
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“In clinical trials, this AE occurred during the first week of treatment and resolved with drug discontinuation (Lembo et al., 2016; VIBERZI (eluxadoline) tablets, for oral use, CIV, 2015).”
BackgroundInfluentialSelf-citationLacy, B. (2018) · Alimentary Pharmacology and Therapeutics · doi:10.1111/apt.14948 · Cited by 36 · see citing works
“has number needed to treat values of 10‐15, while eluxadoline 100 mg has number needed to treat values of 9‐13.(48) The most commonly reported AEs in the pooled eluxadoline population”
BackgroundMethodInfluentialSelf-citationExisting and Emerging Therapies for Managing Constipation and Diarrhea
Bharucha, A., Wouters, M., & Tack, J. (2017) · Current opinion in pharmacology (Print) · doi:10.1016/j.coph.2017.10.015 · Cited by 36 · see citing works
“Six weeks after the first retreatment, all patients were retreated again; again, the response to rifaximin was greater than placebo.[16] Adverse events, primarily headache, upper respiratory tract infection, and abdominal pain, were uncommon and similar between groups.”
BackgroundResultNeuroimmune factors in functional gastrointestinal disorders: A focus on irritable bowel syndrome
Boeckxstaens, G., & Wouters, M. (2017) · Neurogastroenterology and Motility · doi:10.1111/nmo.13007 · Cited by 36 · see citing works
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G-protein–coupled receptors are dynamic regulators of digestion and targets for digestive diseases
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Irritable Bowel Syndrome: Pathophysiology and Current Therapeutic Approaches.
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Acupuncture for Diarrhoea-Predominant Irritable Bowel Syndrome: A Network Meta-Analysis
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Contribution of membrane receptor signalling to chronic visceral pain.
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Chey, W. D., Dove, L. S., Andrae, D., & Covington, P. (2017) · Alimentary Pharmacology and Therapeutics · doi:10.1111/apt.14031 · Cited by 29 · see citing works
“3-month interval (weeks 1–12) and the 6-month interval (weeks 1–26).(14) Within the pooled ITT analysis set, 765 patients (31.”
BackgroundMethodResultInfluentialSelf-citationAbdominal Pain in Inflammatory Bowel Disease: An Evidence-Based, Multidisciplinary Review
Coates, M. D., Clarke, K., Williams, E. D., Jeganathan, N., Yadav, S., Giampetro, D., Gordin, V., Smith, S. E., Vrana, K. E., Bobb, A. D., et al. (2023) · Crohn's & Colitis 360 · doi:10.1093/crocol/otad055 · Cited by 28 · see citing works
“204 Serotonin receptor modulators—”
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An evidence-based update on the diagnosis and management of irritable bowel syndrome
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“Eluxadoline has been evaluated in two placebo-controlled trials recruiting over 2400 patients [98].”
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“142 Eluxadoline is only approved in the United States.”
BackgroundReplacement of current opioid drugs focusing on MOR-related strategies.
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“In phase III studies, it reduced abdominal pain, significantly vs placebo (Brenner et al., 2019; Lacy et al., 2019; Lembo et al., 2016).”
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“2%), one with eluxadoline 75mg and one with eluxadoline 100mg (Lembo et al., 2016).”
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“There was significant improvement in the composite endpoint of abdominal pain and stool consistency with eluxadoline compared to placebo, but no improvement in abdominal pain alone(11).”
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Eluxadoline in irritable bowel syndrome with diarrhea: rationale, evidence and place in therapy
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- Authors
- Lembo, A. J., Lacy, B. E., Zuckerman, M. J., Schey, R., Dove, L. S., Andrae, D. A., Davenport, J. M., McIntyre, G., Lopez, R., Turner, L., & Covington, P. S.
- Affiliations
- Dartmouth College (US)
- Texas Tech University Health Sciences Center (US)
- Temple University (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-01-21
- Volume
- 374
- Issue
- 3
- Pages
- 242-253
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2330377679
- Cited by
- 334
- References
- 0
- Citations by year
- 2026: 21 · 2025: 23 · 2024: 23 · 2023: 19 · 2022: 27 · 2021: 40 · 2020: 31 · 2019: 31 · 2018: 41 · 2017: 49 · 2016: 27 · 2015: 1 · 2014: 1
- FWCI
- 54.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Health Professions › Pharmacy › Infant Health and Development
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- eluxadoline, irritable bowel syndrome with diarrhea, mu-opioid receptor agonists, kappa opioid receptor agonists, delta-opioid receptor antagonists, abdominal pain, stool consistency, drug safety and efficacy, nausea, constipation, adverse events, dose comparison
- MeSH terms
- Adult, Aged, Diarrhea, Dose-Response Relationship, Drug, Female, Humans, Imidazoles, Male, Middle Aged, Pancreatitis, Phenylalanine, Abdominal Pain, Irritable Bowel Syndrome
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